Fetal oxygen deprivation (hypoxia) is a significant cause of human fetal death and of damage to the brain and other organs of surviving infants. For this reason, techniques have been developed which aim to detect signs of fetal hypoxia early enough to allow helpful intervention. In current Western practice, labor and delivery is frequently monitored for signs of fetal distress, especially when the conditions of pregnancy are thought to place the fetus at increased risk. When sufficiently ominous fetal distress signs are observed, rapid induction of labor or surgical delivery by cesarean section are frequently performed in response. Because presently available monitoring devices and methods do not measure fetal oxygen levels directly or do so only intermittently, and/or only at late stages of labor, severe fetal distress sometimes escapes notice. Indirect monitoring techniques also can give misleading indications of fetal oxygen distress (false positives), resulting in surgical intervention that proves to be unnecessary.
The techniques presently employed for fetal monitoring include:
1) Electronic detection and analysis of fetal heartbeat (electrocardiography); PA0 2) Mechanical detection and analysis of fetal heartbeat with stethoscope (auscultation), microphone (phonocardiography), or using ultrasonic waves (ultrasonography); PA0 3) Fetal blood pH measurement by means of an electrode attached to the fetal body; and PA0 4) Fetal blood sampling and analysis (FBS).
All but the last of these techniques do not directly measure fetal oxygen status. Rather, they measure physiological indices which vary in response to fetal hypoxia and other factors. Presently, fetal heartbeat monitoring is the form of fetal monitoring in widest use. Fetal heartbeat monitoring, whether electronic or mechanical, depends upon the observation of a characteristic slowing of the fetal heartbeat (bradycardia) and, in some instruments, alterations in the form of the rhythmic heart signals. Because such alterations in fetal heartbeat can arise from causes other than hypoxia, and because interpretation of the heartbeat signal for evidence of distress can be difficult, this form of monitoring does not provide a completely reliable means of detecting fetal oxygen distress.
A further limitation of fetal heartbeat monitoring is that a clear fetal heartbeat signal is not continuously obtainable from most patients. From 20% to 50% of the time, according to typical reports, no adequate signal is obtainable, and the attending medical personnel are unpredictably left without a reliable indication of fetal condition.
Fetal blood pH tends to decrease (acidity increases) as a result of hypoxia. Fetal pH monitoring, the third technique listed above, is sometimes used in addition to fetal heartbeat monitoring in high-risk pregnancies. However, the use of fetal pH electrodes requires access through the maternal uterine cervix, rupture of the placenta, and the presence of electrical wires connecting the electrode to a measuring device. Further, access is possible only in advanced stages of labor when the cervix is substantially dilated.
Fetal blood sampling, the fourth listed monitoring technique, allows measurements of blood pH and, in principle, of blood oxygen saturation to be made directly. One disadvantage of the method, however, is that isolated individual readings are obtained rather than continuous readings; the technique must be performed repeatedly to avoid false indications for surgery from transient episodes of acidosis or hypoxia that resolve spontaneously. Fetal blood sampling is necessarily invasive, requiring instruments to be inserted through the maternal cervix and small incisions to be made in the fetal scalp (or buttocks, in the case of breech presentations). Complications result from the procedure only infrequently; but the fact that specialized skill and experience in the technique are necessary, along with the limitations described above, have severely limited its clinical use. As with fetal pH monitoring, direct access to the fetus is required, and possible only in late stages of labor.
NMR spectroscopy is described in numerous places including U.S. Pat. No. 4,477,777.
NMR techniques can be used to measure the concentration of various chemical species within the human body, and techniques have been found to elicit signals from specific localized regions within the body. It might, accordingly, be thought that existing NMR methods could be applied to measure the oxygen content of living human fetuses. Such a direct application, however, seems infeasible for reasons including the following:
First, naturally occurring oxygen consists mainly of .sup.16 O, whose nucleus possesses no magnetic moment (hence has gyromagnetic ratio zero) and so cannot be studied by NMR. The natural abundance of .sup.17 O, which does possess a magnetic moment, is only 0.37% and its intrinsic sensitivity is approximately 1.08.times.10.sup.-5 times that of .sup.1 H. As a result, the NMR signal from oxygen within a natural sample or living creature is only some four billionths as strong as the signal from an equal concentration of hydrogen nuclei within it, effectively ruling out any chance of detection by available methods.
It is known, however, that the binding of oxygen atoms to the oxygen- and carbon dioxide- carrying blood protein hemoglobin so alters the distribution of electrons around the iron atoms within the protein's heme groups, and so alters the conformation of the four amino acid chains that comprise the protein molecule, that a number of proton and carbon resonances are detectably shifted as a result. Consequently, it is feasible to determine the oxygen saturation of hemoglobin by measuring the amplitudes of such resonances and comparing them with the amplitudes of other resonances whose position happens not to be shifted upon oxygen binding (whose chemical shift, that is, is unaffected by normal oxygen binding to the hemoglobin molecule).
The NMR signal from blood within the body of a pregnant human female originates mainly in maternal rather than fetal blood, because the volume of fetal blood comprises no more than 5-10% of the total. Since the oxygenation level of the maternal blood gives little, if any, indication of fetal oxygen levels, means must be found to isolate a signal specifically representative of fetal oxygenation. Existing art offers two methods for distinguishing NMR signals from specified spatial regions: magnetic resonance imaging (MRI) and spatial localization through the use of shaped magnetic fields and/or specialized radio frequency antennas. MRI, whether accomplished by pulse-gradient techniques, focused magnetic fields (FONAR), or otherwise, extracts NMR signals from individual small volume elements such as cubes, or thin two-dimensional sections such as flat planes, and from a succession of these signals, constructs a three-dimensional representation of the object being examined. All such methods are unsuitable for obtaining NMR spectroscopic information from circulating blood for two reasons. First, signal-to-noise ratios decline to impractically small levels for NMR spectroscopy as the effective sampling volume is reduced to the size of volume elements employed in MRI. Second, the relaxation times characteristic of useful resonances in blood are too long: excited nuclei spend considerably less time within an imaging volume element than the characteristic relaxation periods as a result of normal blood circulation. Excited nuclei will therefore have left a volume element before an NMR signal can be obtained from them.
Spatial localization of NMR signals can be accomplished through the use of static-field magnets designed to produce a homogeneous field only within a limited region, and whose field outside the region of interest increases or declines rapidly. As a result, resonance conditions can occur only within the homogeneous region. A form of spatial localization can also be achieved through the use of specially shaped radio frequency transmitting and receiving antennas (or combination transmitting-receiving antennas), such as circular or semi-toroidal surface coils, which transmit and receive signals efficiently only from nearby regions. Such a coil, placed against the surface of a human body, typically conveys NMR signals only from a region within the body of dimensions comparable to those of the coil. The use of shaped magnetic fields and surface coils can be combined for localized NMR spectroscopy. Existing methods, however, provide no means for such localized spectroscopy where the target volume is constantly changing shape and position, as does the fetus within a pregnant woman. Unless the location of the fetus with respect to the NMR apparatus were continuously determined, and the shape of the constant-field region of the static magnetic field somehow adjusted to precisely conform to the fetus, the NMR signals would contain an unknown and constantly varying contribution from maternal tissues and blood.
Because NMR can in principle be used to examine chemical reactions within the interior of the body, non-invasively and with essentially no known hazards, and because present fetal monitoring techniques are inadequate, the motivation remains to discover methods for using NMR to monitor fetal physiology.